Nonsyndromic Craniosynostosis: Phenotype/Genotype Study

非综合征性颅缝早闭：表型/基因型研究

• 批准号: 9308677
• 负责人: Simeon A Boyadjiev Boyd
• 金额: $ 69.78万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308677
• 关键词: Affect; Animals; BMP2 gene; Biological; Biological Assay; Blood; Candidate Disease Gene; Case-Control Studies; Cells; Centers for Disease Control and Prevention (U.S.); Characteristics; Chromosomes, Human, Pair 20; Chromosomes, Human, Pair 7; Classification; Clinical; Clinical Data; Collaborations; Collection; Congenital Abnormality; Craniosynostosis; Data; Defect; Developmental Delay Disorders; Dizygotic Twins; Educational workshop; Environmental Exposure; Environmental Risk Factor; Epidemiology; Epigenetic Process; Etiology; Family; Family Study; Female; Fibroblast Growth Factor Receptors; Funding; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Individual; Infant; International; Investigation; Joint structure of suture of skull; Leadership; Live Birth; Molecular; Molecular Genetics; Mothers; Newborn Infant; Not Hispanic or Latino; Parents; Participant; Phenotype; Physical Examination; Positioning Attribute; Pregnancy; Prevention; Prevention strategy; Preventive Intervention; Primary Prevention; Recommendation; Recurrence; Reporting; Research; Research Infrastructure; Residual state; Resources; Risk; Role; Sampling; Scientist; Site; Skeletal Development; Specimen; Spottings; Surgical sutures; Syndrome; System; Tobacco; United States; United States National Institutes of Health; Variant; Work; Zebrafish; base; blastomere structure; case control; cell motility; cell transformation; cranium; disorder prevention; gene discovery; genetic risk factor; genetic variant; genome wide association study; insight; interest; male; mouse model; population based; premature; public health relevance; risk variant; scaffold

DESCRIPTION (provided by applicant): Craniosynostosis (CS), the premature fusion of one or more cranial sutures, is a common defect occurring in 1 in 2,500 live births. About 85% of infants with CS present as nonsyndromic (i.e., without unrelated, major birth defects or developmental delay). Nonsyndromic CS (NCS) is a heterogeneous condition with presumed multifactorial etiology; however, after nearly one-half century of study, its causes remain largely unknown. As such, primary prevention strategies for this defect are limited. Through our International Craniosynostosis Consortium (ICC), we have advanced understanding of the genetic etiology for the most common CS subtype, sagittal NCS (sNCS). Specifically, with our previous funding (R01 DE016866), we successfully conducted the first genome-wide association study for sNCS and identified robust associations to loci near BMP2 (rs1884302; P=1.1x10-39; OR=4.38) and within BBS9 (rs10262453; P=5.6x10-20; OR=0.24), both biologically plausible genes with a role in skeletal development. Building on our work, we propose to use a scaffold approach, moving from this "discovery" to "confirmation" through sequencing and functional assays; putative causative variants identified will be further characterized using zebrafish and mouse models. We hypothesize that identified variants contribute to the risk of sNCS by altering gene expression. Using the ICC infrastructure, we also propose to investigate metopic NCS (mNCS). Both sNCS and mNCS affect the midline sutures of the skull, are more likely to occur among non-Hispanic whites, and show a male excess. Given these similarities, we hypothesize that sNCS and mNCS may share common causative variants, and propose an array-based family study of mNCS case-parent trios and replication with an independent case-control sample; sequencing and functional assays of candidate genes and loci will be conducted together with those for sNCS. Subsequently, we propose to move from "confirmation" to "interaction" with environmental exposures, the apex of our scaffold approach. We will investigate environmental exposures and gene-environmental interaction effects associated with each subtype using maternal reports of pregnancy exposures obtained from the ICC and maternal reports and biological specimens obtained from the National Birth Defects Prevention Study (NBDPS). The NBDPS is the largest case-control study of birth defects in the United States. It uses population- based surveillance and systematic case review and classification to enumerate infants with one of over 30 major defects, including NCS. The NBDPS provides a rich resource to investigate environmental exposures and gene-environmental interaction effects. In summary, we propose comprehensive clinical, epidemiological, and molecular characterization of sNCS and mNCS through the collaborative efforts of clinicians and scientists with demonstrated expertise and long-standing interests in NCS. Given our accomplishments and substantial resources of the ICC and NBDPS, we are well-positioned to successfully complete the proposed research and contribute critical insights into the multifactorial etiology of sNCS and mNCS.

描述（由申请人提供）： 颅缝早闭 (CS)，即一根或多根颅缝的过早融合，是一种常见缺陷，每 2,500 名活产儿中就有 1 人发生这种情况。大约 85% 的 CS 婴儿表现为非综合征（即没有无关的严重出生缺陷或发育迟缓）。非综合征性 CS (NCS) 是一种异质性疾病，推测其病因有多种因素。然而，经过近半个世纪的研究，其原因在很大程度上仍然存在 未知。因此，针对这种缺陷的一级预防策略是有限的。通过我们的国际颅缝早闭联盟 (ICC)，我们对最常见的 CS 亚型矢状 NCS (sNCS) 的遗传病因有了深入的了解。具体来说，利用我们之前的资助 (R01 DE016866)，我们成功地进行了第一个 sNCS 全基因组关联研究，并确定了与 BMP2 附近的位点 (rs1884302; P=1.1x10-39; OR=4.38) 和 BBS9 内的位点 (rs10262453; P=5.6x10-20; OR=0.24) 之间的强有力的关联，两者在生物学上都是如此。 在骨骼发育中发挥作用的合理基因。在我们工作的基础上，我们建议使用支架方法，通过测序和功能分析从“发现”转向“确认”；将使用斑马鱼和小鼠模型进一步表征所确定的假定致病变异。我们假设已识别的变异通过改变基因表达来增加 sNCS 的风险。使用 ICC 基础设施，我们还建议研究同位素 NCS (mNCS)。 sNCS 和 mNCS 都会影响颅骨中线缝线，更可能发生在非西班牙裔白人中，并且表现出男性过多。鉴于这些相似性，我们假设 sNCS 和 mNCS 可能具有共同的致病变异，并提出一项基于芯片的 mNCS 病例-父母三重奏家族研究，并使用独立的病例对照样本进行复制；候选基因和基因座的测序和功能测定将与 sNCS 的测序和功能测定一起进行。随后，我们建议从“确认”转向与环境暴露的“互动”，这是我们脚手架方法的顶点。我们将使用从 ICC 获得的孕期暴露孕产妇报告以及从国家出生缺陷预防研究 (NBDPS) 获得的孕产妇报告和生物样本来调查与每种亚型相关的环境暴露和基因-环境相互作用影响。 NBDPS 是美国最大的出生缺陷病例对照研究。它使用基于人群的监测和系统病例审查和分类来列举患有 30 多种主要缺陷之一的婴儿，包括 NCS。 NBDPS 提供了丰富的资源来研究环境暴露和基因-环境相互作用的影响。总之，我们建议通过对 NCS 具有专业知识和长期兴趣的临床医生和科学家的共同努力，对 sNCS 和 mNCS 进行全面的临床、流行病学和分子特征分析。鉴于我们的成就以及 ICC 和 NBDPS 的大量资源，我们完全有能力成功完成拟议的研究，并为 sNCS 和 mNCS 的多因素病因学提供重要见解。